Teratogen screening using transcriptome profiling of differentiating human embryonic stem cells.
Bottom Line: To examine teratogenic effects on early human development we performed non-biased expression profiling of differentiating human embryonic and induced pluripotent stem cells treated with several drugs--ethanol, lithium, retinoic acid (RA), caffeine and thalidomide, which is known to be highly species specific.Our results point to the potency of specific teratogens and their affected tissues and pathways.Specifically, we could show that ethanol caused dramatic increase in endodermal differentiation, RA caused misregulation of neural development and thalidomide affected both these processes.
Affiliation: Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem, Israel.Show MeSH
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Mentions: Ethanol treatment clearly caused elevation of AFP staining, as was expected from the dramatic increase in mRNA levels shown by the microarray analysis. Interestingly, there was also dramatic increase in SOX17 staining (Fig. 4A). This would suggest that ethanol acts to increase differentiation of HESCs into the endodermal lineage, a subpopulation of which continues to differentiate into AFP-expressing early hepatic-like cells. The most dramatic effect of RA treatment was in the significant overexpression of the Hox genes (Fig. 3), and the misexpression of brain specific genes (Fig. 2), such that there was both significant up- and down-regulation of these genes. HOXA1 in particular was highly overexpressed at the mRNA level (13.6-fold, P-value = 0.0003). Indeed, at the protein level we can see similar increase in HOXA1 abundance, together with NCAM1 (Fig. 4B), indicating significant effects of RA on neuronal differentiation.
Affiliation: Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem, Israel.